Type II diabetes is a health problem of 20% of the elderly population in the U.S. The aims of this project are: to define regulatory signals controlling insulin secretion from beta cells of the pancreas; to study the mechanism of action of gastrointestinal hormones called incretins ( e.g. glucagon-like peptides [GLP] and glucose insulinotropic peptide [GIP]) on stimulation of insulin secretion; and to study directly changes in insulin secretion during aging. These studies have required the development of an in vitro system for the study of insulin secretion. Freshly isolated pancreatic beta cells and several pancreatic insulinoma cell lines were screened using reverse hemolytic plaque assay and radioimmunoassay for insulin. Freshly isolated beta cells were used to study the effect of extracellular matrix prepared from young and old animals on the insulin secretion. The best insulinoma cell line was chosen to study the effect of incretins such as GLP and GIP on insulin secretion. The information on incretin effects obtained from these in vitro study can now be applied to in vivo systems such as studies in monkey and in man. The GLP receptor has been cloned from rat pancreas and the clone is available to us. Transfection of GLP receptor sequences into different cell lines will allow us to study further the signal transduction involved in GLP action. Further, the screening of peptides, with structural similarity to GLP will allow the understanding of structure-function relationship and the development of new therapeutic agents for type II diabetes.